Octreotide is a highly potent and pharmacologically selective analog of somatostatin. It inhibits growth hormone for long duration and is therefore indicated for acromegaly to control and reduce the plasma level of growth hormone. The presence of D-Phe at the N-terminal and an amino alcohol at the C-terminal, along with D-tryptophan and a cyclic structure makes it very resistant to metabolic degradation.
The only solution synthesis reported in literature is by Bauer, W. and Pless, J. in Pat. No. U.S. Pat. No. 4,395,403 and EP029579.
Several solid phase syntheses have been subsequently described viz. Patent Nos. EP0953577A1 and U.S. Pat. No. 5,889,146 and in various research publications. Mergler et al (Proceedings of the 12th American Peptide Symposium) have used aminomethyl resin and Fmoc-butyl protection scheme for synthesis of octreotide. Alsina et al. Tetrahedron Letters, 38, 883, 1997) have used an active carbonate resin and Boc-Bzl protection scheme, necessitating the use of hydrogen fluoride/anisole for final deprotection. Edwards et al (J. Med. Chem., 37, 3749, 1994)) have described another synthesis using Fmoc-butyl protection and HMP resin, and Berta et al (EP 0 953 577A1) a synthesis using 2-chlorotrityl-type resin and Fmoc-butyl protection scheme.
All the solid phase syntheses described are useful only for the manufacture of small quantities of octreotide (100-300 mg). These procedures are not suitable for commercial manufacture of octreotide because they use costly resins and costly Fmoc-butyl protected amino acids in 2 to 4 times excess at every step. In one synthesis the final deprotection is carried out with hydrogen fluoride, a destructive and hazardous reagent.
The solution synthesis described by Bauer and Pless in Patent No. U.S. Pat. No. 4,395,403 and EP029579 uses BTFA/TFA to remove the methoxybenzyl group protecting the thiol group of cysteine, followed by cyclization. Decomposition of tryptophan is frequently known to occur during such harsh acid treatment for removal of protecting groups.